Estrogens are well-known endocrine regulators in the cellular processes involved in the development and maintenance of the reproductive system. Estrogens have also been shown to have important effects in many non-reproductive tissues such as bone, liver, the cardiovascular system, and the central nervous system. Estrogen receptors are ligand-activated transcription factors and belong to the nuclear hormone receptor subfamily. Upon binding ligand, these receptors dimerize and can activate gene transcription either by directly binding to specific sequences on DNA known as response elements or by interacting with transcription factors (such as API) which in turn bind directly to specific DNA sequences. Additionally, it is now becoming apparent that estrogens may mediate their effects via kinase-mediated signalling cascade, though much of this work is still experimental. Kousteni et al., Journal of Clinical Investigation, (2003), 111, 1651-1664.
Historically estrogens were believed to manifest their biological activity through a single estrogen receptor, now termed estrogen receptor alpha (ERα). More recently, however, there was the discovery of second subtype of estrogen receptor, termed estrogen receptor beta (ERβ or ER beta). See, Kuiper et al., WO 97/09348 and Kuiper et al., Cloning of a Novel Estrogen Receptor Expressed in Rat Prostate and Ovary, Proc. Natl. Acad. Sci. U.S.A., 1996, pp. 5925-5930. ERβ is expressed in humans. See, Mosselman et al., ERβ: Identification and Characterization of a Novel Human Estrogen Receptor, FEBR S Lett., 1996, pp. 49-53. The discovery of this second subtype of estrogen receptor significantly increased the biological complexity of estrogen signalling.
The tissue distribution of ERβ has been well mapped in the rodent and it is not coincident with ERα. Tissues such as the mouse uterus and ovary express predominantly ERα, whereas non reproductive organs e.g. the mouse lung express predominantly ERβ. See Couse, et al., Endocrinology 138: 4613-4621 (1997), Kuiper, et al., Endocrinology 138: 863-870 (1997). Even within the same organ, the distribution of ERα and ERβ can be compartmentalized. For example, in the rat ovary, ERβ is highly expressed in the granulosa cells and ERα is restricted to the thecal and stromal cells. See Sar and Welsch, Endocrinology 140: 963-971 (1999). However, there are examples where the receptors are coexpressed and there is evidence in vitro studies that ERα and ERβ can form heterodimers. See Cowley, et al., Journal of Biological Chemistry 272: 19858-19862 (1997).
The most potent endogenous estrogen is 17β-estradiol. A large number of compounds have been described that either mimic or block the activity of 17β-estradiol. Compounds having roughly the same biological effects as 17β-estradiol are referred to as “estrogen receptor agonists”. Those which block the effects of 17β-estradiol, when given in combination with it, are called “estrogen receptor antagonists”. In reality, there is a continuum between estrogen receptor agonist and estrogen receptor antagonist activity and some compounds behave as estrogen receptor agonists in some tissues but estrogen receptor antagonists in others. Compounds with mixed activity are called selective estrogen receptor modulators (SERMS) and may be therapeutically useful agents. The precise reason why the same compound can have cell-specific effects has not been elucidated, but the differences in receptor conformation and/or in the milieu of coregulatory proteins have been suggested.